T-cell-mediated lympholysis was generated in vitro against trinitrophenyl-(TNP-) modified syngeneic murine spleen cells. The cytotoxic effectors generated are specific for both the modifying agent and for self major histocompatibility complex (MHC) products mapping in the K or D regions of the H-2 complex. Specificity of the effectors was such that they could not lyse H-2-matched targets in which the TNP group was presented on the targets by insertion of a TNP-fatty acid-dextran conjugate into the cell membrane. However, effectors could be generated by culturing spleen cells with TNP coupled to soluble proteins. These effectors were also restricted to lyse TNP-modified K or D matched targets. Cultures primed in vitro with TNP-modified syngeneic cells generated secondary effectors only if restimulated with TNP-modified cells sharing K or D with the primary stimulators. Secondary proliferative responses were induced only with TNP-modified cells sharing K, D, or I regions with the primary stimulators. The ability of mouse spleen cells to generate effectors against TNP-H-2Dd was shown to be controlled by at least two H-2 linked immune response genes--one mapping between the I-A and I-J subregions and one to the left of the I region of the H-2 complex. BIBLIOGRAPHIC REFERENCES: Shearer, G. M., Rehn, T. G. and Schmitt-Verhulst, A.-M.: Role of the murine major histocompatibility complex in the induction of cell-mediated lympholysis to chemically modified autologous lymphocytes. Transplant. Rev. 29: 222-248, 1976. Schmitt-Verhulst, A.-M. and Shearer, G. M.: H-2 linked bifunctional genetic control of cell-mediated lympholysis to TNP-modified autologous cell surfaces. In Eijsvoogel, V. O. (Ed.): Leukocyte Membrane Determinants Regulating Immune Reactivity. New York, Academic Press, 1976, pp. 431-440.